tbuckley/cabot-search huggingface dataset:
Prevalence of dementia in Latin America and Caribbean countries: Systematic review and meta-analyses exploring age, sex, rurality, and education as possible determinants
Authors: Fabiana Ribeiro, Ana C. Teixeira-Santos, Paulo Caramelli, Anja K. Leist
Journal: Ageing Research Reviews (2022)

Studies have shown that the prevalence of dementia in Latin America and the Caribbean (LAC) may be higher than in high-income countries. Thus, we sought to systematically analyse the prevalence of dementia and explore possible drivers that lead to this disparity in LAC countries.We searched Pubmed, Web of Knowledge, Scopus, Lilacs, and SciELO for studies on dementia in LAC countries published in English, Spanish, and Portuguese. Random-effects model was applied.Thirty-one studies from 17 LAC countries were included. Pooled prevalence of all-cause dementia was 10.66%. Further analyses with studies providing raw prevalence by sex, area, and educational level showed a higher prevalence for women (8.97%) than for men (7.26%). Also, dementia prevalence was higher for rural than urban residents (7.71% vs 8.68%, respectively). Participants without formal education presented more than double the prevalence of dementia (21.37%) compared to those with at least one year of formal education (9.88%). Studies with more recent data collection showed higher dementia prevalence.Our findings suggest a high global dementia prevalence in LAC countries and an unequal burden of dementia for women, lower-educated, and rural residents. Secular increases in dementia prevalence call for greater public health efforts for preventative actions.
Macrophages as a therapeutic target to promote diabetic wound healing
Authors: Maryam Sharifiaghdam, Elnaz Shaabani, Reza Faridi-Majidi, Stefaan C. De Smedt, Kevin Braeckmans, Juan C. Fraire
Journal: Molecular Therapy (2022)

It is well‏ ‏established that macrophages are key regulators of wound healing, displaying impressive plasticity and an evolving phenotype, from an aggressive pro-inflammatory or "M1" phenotype to a pro-healing or "M2" phenotype, depending on the wound healing stage, to ensure proper healing. Because dysregulated macrophage responses have been linked to impaired healing of diabetic wounds, macrophages are being considered as a therapeutic target for improved wound healing. In this review, we first discuss the role of macrophages in a normal skin wound healing process and discuss the aberrations that occur in macrophages under diabetic conditions. Next we provide an overview of recent macrophage-based therapeutic approaches, including delivery of ex-vivo-activated macrophages and delivery of pharmacological strategies aimed at eliminating or re-educating local skin macrophages. In particular, we focus on strategies to silence key regulator genes to repolarize wound macrophages to the M2 phenotype, and we provide a discussion of their potential future clinical translation. It is well‏ ‏established that macrophages are key regulators of wound healing, displaying impressive plasticity and an evolving phenotype, from an aggressive pro-inflammatory or "M1" phenotype to a pro-healing or "M2" phenotype, depending on the wound healing stage, to ensure proper healing. Because dysregulated macrophage responses have been linked to impaired healing of diabetic wounds, macrophages are being considered as a therapeutic target for improved wound healing. In this review, we first discuss the role of macrophages in a normal skin wound healing process and discuss the aberrations that occur in macrophages under diabetic conditions. Next we provide an overview of recent macrophage-based therapeutic approaches, including delivery of ex-vivo-activated macrophages and delivery of pharmacological strategies aimed at eliminating or re-educating local skin macrophages. In particular, we focus on strategies to silence key regulator genes to repolarize wound macrophages to the M2 phenotype, and we provide a discussion of their potential future clinical translation.
Monkeypox outbreak, will it affect surgery services? – Correspondence
Authors: Gonzalo Andrés Domínguez Alvarado, Jorge Andrés Rativa Hernández, Andrés Felipe Hortua Moreno, Jesús Manuel Eljaiek Orozco, Jessica Johana Rodríguez Cotamo, Luis Ernesto López Gómez, Sergio Serrano Gómez
Journal: International Journal of Surgery (2022)
Pre-existing partner-drug resistance to artemisinin combination therapies facilitates the emergence and spread of artemisinin resistance: a consensus modelling study
Authors: Oliver J Watson, Bo Gao, Tran Dang Nguyen, Thu Nguyen-Anh Tran, Melissa A Penny, David L Smith, Lucy Okell, Ricardo Aguas, Maciej F Boni
Journal: The Lancet Microbe (2022)
Five Percent Variant Allele Frequency Is a Reliable Reporting Threshold for TP53 Variants Detected by Next Generation Sequencing in Chronic Lymphocytic Leukemia in the Clinical Setting
Authors: Tatjana Pandzic, Claes Ladenvall, Marie Engvall, Mattias Mattsson, Monica Hermanson, Lucia Cavelier, Viktor Ljungström, Panagiotis Baliakas
Journal: HemaSphere (2022)

The clinical significance of small TP53 clones detected with next generation sequencing (NGS) in chronic lymphocytic leukemia is an issue of active debate. According to the official guidelines, treatment decisions should be guided only by variants with variant allele frequency (VAF) ≥10%. We present data on 325 consecutive patients with chronic lymphocytic leukemia analyzed with NGS. In total 47 pathogenic/likely pathogenic (P/LP), TP53 variants were detected in 26 patients (8%). Eleven of these (23%) were in the 5% to 10% VAF range and reported according to our institutional policy. All TP53 variants in the 5% to 10% VAF range were confirmed (100% concordance) with a second NGS panel. Our results where further validated with the performance of Sanger sequencing and digital droplet PCR (ddPCR). In 12 patients with available fluorescence in situ hybridization data and TP53 mutations within 5% to 10% VAF, deletion of chromosome 17p (del(17p)) was detectable in only 1 patient. We propose a robust diagnostic algorithm, which allows the safe detection and reporting of TP53 variants with VAF down to 5% in the clinical setting. Our study provides evidence that NGS is equally potent to detect variants with VAF 5% to 10% compared to those with VAF 10% to 15%, highlighting the urgent need for harmonization of NGS methodologies across diagnostic laboratories.
Peptide–drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope?
Authors: Chen Fu, Lifeng Yu, Yuxi Miao, Xinli Liu, Zhaojin Yu, Minjie Wei
Journal: Acta Pharmaceutica Sinica B (2022)

Peptide-drug conjugates (PDCs) are the next generation of targeted therapeutics drug after antibody-drug conjugates (ADCs), with the core benefits of enhanced cellular permeability and improved drug selectivity. Two drugs are now approved for market by US Food and Drug Administration (FDA), and in the last two years, the pharmaceutical companies have been developing PDCs as targeted therapeutic candidates for cancer, coronavirus disease 2019 (COVID-19), metabolic diseases, and so on. The therapeutic benefits of PDCs are significant, but poor stability, low bioactivity, long research and development time, and slow clinical development process as therapeutic agents of PDC, how can we design PDCs more effectively and what is the future direction of PDCs? This review summarises the components and functions of PDCs for therapeutic, from drug target screening and PDC design improvement strategies to clinical applications to improve the permeability, targeting, and stability of the various components of PDCs. This holds great promise for the future of PDCs, such as bicyclic peptide‒toxin coupling or supramolecular nanostructures for peptide-conjugated drugs. The mode of drug delivery is determined according to the PDC design and current clinical trials are summarised. The way is shown for future PDC development.
The m6A methyltransferase Mettl3 deficiency attenuates hepatic stellate cell activation and liver fibrosis
Authors: Yanli Li, Xinmei Kang, Zhuowei Zhou, Lijie Pan, Huaxin Chen, Xiaoqi Liang, Jiajie Chu, Shuai Dong, Chang Liu, Shanshan Yu, Dan Tu, Yiwang Zhang, Mian Ge, Wenjie Chen, Yan Xu, Qi Zhang
Journal: Molecular Therapy (2022)

Activation of hepatic stellate cells (HSCs) is a central driver of liver fibrosis. Previous investigations have identified various altered epigenetic landscapes during the cellular progression of HSC activation. N6-methyladenosine (m6A) is the most abundant internal RNA modification in eukaryotic cells and is dynamically regulated under various physiological and pathophysiological conditions. However, the functional role of Mettl3-mediated m6A in liver fibrosis remains elusive. Here, we found that the HSC-specific knockout of m6A methyltransferase Mettl3 suppressed HSC activation and significantly alleviated liver fibrosis. Multi-omics analysis of HSCs showed that Mettl3 depletion reduced m6A deposition on mRNA transcripts of Lats2 (a central player of the Hippo/YAP signaling pathway) and slowed down their degradation. Elevated Lats2 increased phosphorylation of the downstream transcription factor YAP, suppressed YAP nuclear translocation, and decreased pro-fibrotic gene expression. Overexpressing YAP mutant resistant to phosphorylation by Lats2 partially rescued the activation and pro-fibrotic gene expression of Mettl3-deficient HSCs. Our study revealed that disruption of Mettl3 in HSCs mitigated liver fibrosis by controlling the Hippo/YAP signaling pathway, providing potential therapeutic strategies to alleviate liver fibrosis by targeting epitranscriptomic machinery. Activation of hepatic stellate cells (HSCs) is a central driver of liver fibrosis. Previous investigations have identified various altered epigenetic landscapes during the cellular progression of HSC activation. N6-methyladenosine (m6A) is the most abundant internal RNA modification in eukaryotic cells and is dynamically regulated under various physiological and pathophysiological conditions. However, the functional role of Mettl3-mediated m6A in liver fibrosis remains elusive. Here, we found that the HSC-specific knockout of m6A methyltransferase Mettl3 suppressed HSC activation and significantly alleviated liver fibrosis. Multi-omics analysis of HSCs showed that Mettl3 depletion reduced m6A deposition on mRNA transcripts of Lats2 (a central player of the Hippo/YAP signaling pathway) and slowed down their degradation. Elevated Lats2 increased phosphorylation of the downstream transcription factor YAP, suppressed YAP nuclear translocation, and decreased pro-fibrotic gene expression. Overexpressing YAP mutant resistant to phosphorylation by Lats2 partially rescued the activation and pro-fibrotic gene expression of Mettl3-deficient HSCs. Our study revealed that disruption of Mettl3 in HSCs mitigated liver fibrosis by controlling the Hippo/YAP signaling pathway, providing potential therapeutic strategies to alleviate liver fibrosis by targeting epitranscriptomic machinery.
Viewing animal migration through a social lens
Authors: Ellen O. Aikens, Iris D. Bontekoe, Lara Blumenstiel, Anna Schlicksupp, Andrea Flack
Journal: Trends in Ecology & Evolution (2022)

Evidence of social learning is growing across the animal kingdom. Researchers have long hypothesized that social interactions play a key role in many animal migrations, but strong empirical support is scarce except in a few unique systems and species. In this review, we aim to catalyze advances in the study of social migrations by synthesizing research across disciplines and providing a framework for understanding when, how, and why social influences shape the decisions animals make during migration. Integrating research across the fields of social learning and migration ecology will advance our understanding of the complex behavioral phenomena of animal migration and help to inform conservation of animal migrations in a changing world.
Association of entry into hospice or palliative care consultation during acute care hospitalization with subsequent antibiotic utilization
Authors: Alexandre R. Marra, Gosia S. Clore, Erin Balkenende, Cassie Cunningham Goedken, Daniel J. Livorsi, Michihiko Goto, Mary S. Vaughan-Sarrazin, Ann Broderick, Eli N. Perencevich
Journal: Clinical Microbiology and Infection (2022)
Association between leucocyte telomere length and the risk of atrial fibrillation: An updated systematic review and meta-analysis
Authors: Yi Zheng, Nan Zhang, Yueying Wang, Feng Wang, Guangping Li, Gary Tse, Tong Liu
Journal: Ageing Research Reviews (2022)

Advancing age is the most important risk factor of atrial fibrillation (AF). The shortening of telomere length is a biomarker of biologic aging. There is an increasing body of evidence that leucocyte telomere length (LTL) is associated with the risk of AF development. However, the results in these studies were controversial. The current systematic review and meta-analysis was conducted to examine the role of LTL in predicting the incidence of AF. Observational studies reporting the association between LTL and the risk of AF were retrieved through 25th June, 2022 from PubMed and Embase. A total of twelve studies including 18,293 patients were included in the present analysis. Leucocyte telomere shortening was found to be an independent predictor of AF as a continuous variable in both univariate [OR:2.14; 95%CI(1.48,3.10); P < 0.0001] and multivariate analyses [OR:1.41;95%CI(1.11,1.79); P = 0.005], as well as categorical variable in multivariate analysis [OR:1.53; 95%CI(1.04,2.27); P = 0.03]. Furthermore, leucocyte telomere shortening was significantly associated with recurrent AF [OR:4.32;95%CI(2.42,7.69); P < 0.00001] but not new-onset AF [OR:1.14; 95%CI(0.90,1.45); P = 0.29]. Leucocyte telomere shortening was also associated with an increased risk of persistent AF [OR:14.73;95%CI (3.16,68.67); P = 0.0006] and paroxysmal AF [OR:2.74;95%CI(1.45,5.18); P = 0.002]. Besides, LTL was an independent predictor for progression from paroxysmal AF to persistent AF [OR:3.2;95%CI(1.66,6.18); P = 0.0005]. Differences between males [OR:1.99; 95%CI(1.29,3.06); P = 0.002] and females [OR:0.86; 95%CI (0.29,2.56);P = 0.79] were observed. Leucocyte telomere shortening predicts the risk of AF, especially recurrent AF. The predictive value is more prominent in males than in females. Shortening in LTL can predict the progression from paroxysmal to persistent AF.
Impeding the combination of astrocytic ASCT2 and NLRP3 by talniflumate alleviates neuroinflammation in experimental models of Parkinson's disease
Authors: Yang Liu, Ting Liu, Yuanzhang Zhou, Wenjie Li, Min Wang, Nanshan Song, Wenbin Zhang, Jingwei Jiang, Shengtao Yuan, Jianhua Ding, Gang Hu, Ming Lu
Journal: Acta Pharmaceutica Sinica B (2022)

Alanine-serine-cysteine transporter 2 (ASCT2) is reported to participate in the progression of tumors and metabolic diseases. It is also considered to play a crucial role in the glutamate-glutamine shuttle of neuroglial network. However, it remains unclear the involvement of ASCT2 in neurological diseases such as Parkinson's disease (PD). In this study, we demonstrated that high expression of ASCT2 in the plasma samples of PD patients and the midbrain of MPTP mouse models is positively correlated with dyskinesia. We further illustrated that ASCT2 expressed in astrocytes rather than neurons significantly upregulated in response to either MPP+ or LPS/ATP challenge. Genetic ablation of astrocytic ASCT2 alleviated the neuroinflammation and rescued dopaminergic (DA) neuron damage in PD models in vitro and in vivo. Notably, the binding of ASCT2 to NLRP3 aggravates astrocytic inflammasome-triggered neuroinflammation. Then a panel of 2513 FDA-approved drugs were performed via virtual molecular screening based on the target ASCT2 and we succeed in getting the drug talniflumate. It is validated talniflumate impedes astrocytic inflammation and prevents degeneration of DA neurons in PD models. Collectively, these findings reveal the role of astrocytic ASCT2 in the pathogenesis of PD, broaden the therapeutic strategy and provide a promising candidate drug for PD treatment.
Second Booster BNT162b2 Restores SARS-CoV-2 Humoral Response in Patients With Multiple Myeloma, Excluding Those Under Anti-BCMA Therapy
Authors: Ioannis Ntanasis-Stathopoulos, Vangelis Karalis, Maria Gavriatopoulou, Panagiotis Malandrakis, Aimilia D. Sklirou, Evangelos Eleutherakis-Papaiakovou, Magdalini Migkou, Maria Roussou, Despina Fotiou, Harry Alexopoulos, Foteini Theodorakakou, Efstathios Kastritis, Vassiliki A. Iconomidou, Ioannis P. Trougakos, Meletios A. Dimopoulos, Evangelos Terpos
Journal: HemaSphere (2022)

COVID-19 vaccination leads to a less intense humoral response in patients with multiple myeloma (MM) compared with healthy individuals, whereas the SARS-CoV-2-specific immunity fades over time. The purpose of this study was to explore the kinetics of SARS-CoV-2 neutralizing antibodies (NAbs) in patients with MM after vaccination with the BNT162b2 mRNA vaccine, focusing on their response before (B4D) and at 1 month after the fourth vaccination (M1P4D). Overall, 201 patients with a median age of 67 years were included, whereas 114 (56.7%) were men. The median NAbs levels B4D were 80.0% (±3.5%) and at M1P4D they increased to a median value of 96.1% (±3.7%). The NAb values at M1P4D were similar to those at 1 month post the third dose and superior to all previous timepoints. At M1P4D, the NAbs levels of all the treatment groups increased, apart from the anti-BCMA group. A significant increase in median NAbs values was observed for those receiving CD38-based treatment (n = 43, from 71.0% B4D to 96.0% at M1P4D) and those who did not receive CD38- or BCMA-targeted therapy (n = 137, from 89.6% B4D to 96.3% at M1P4D). Regarding the patients under BCMA-based therapy (n = 21), there was no remarkable increase in NAbs values following the second booster shot (from 3.0% B4D to 4.0% at M1P4D). In conclusion, booster vaccination with the BNT162b2 results in a substantially improved humoral response against SARS-CoV-2 in patients with MM. Anti-BCMA treatment remains an adverse predictive factor for NAbs response; thus, tailored prevention measures should be considered for this patient subgroup.
2021 Thalassaemia International Federation Guidelines for the Management of Transfusion-dependent Thalassemia
Authors: Dimitrios Farmakis, John Porter, Ali Taher, Maria Domenica Cappellini, Michael Angastiniotis, Androulla Eleftheriou
Journal: HemaSphere (2022)

Beta-thalassemia and particularly its transfusion-dependent form (TDT) is a demanding clinical condition, requiring life-long care and follow-up, ideally in specialized centers and by multidisciplinary teams of experts. Despite the significant progress in TDT diagnosis and treatment over the past decades that has dramatically improved patients’ prognosis, its management remains challenging. On one hand, diagnostic and therapeutic advances are not equally applied to all patients across the world, particularly in several high-prevalence eastern regions. On the other, healthcare systems in low-prevalence western countries that have recently received large numbers of migrant thalassemia patients, were not ready to address patients’ special needs. Thalassaemia International Federation (TIF), a global patient-driven umbrella federation with 232 member-associations in 62 countries, strives for equal access to quality care for all patients suffering from thalassemia or other hemoglobinopathies in every part of the world by promoting education, research, awareness, and advocacy. One of TIF’s main actions is the development and dissemination of clinical practice guidelines for the management of these patients. In 2021, the fourth edition of TIF’s guidelines for the management of TDT was published. The full text provides detailed information on the management of TDT patients and the clinical presentation, pathophysiology, diagnostic approach, and treatment of disease complications or other clinical entities that may occur in these patients, while also covering relevant psychosocial and organizational issues. The present document is a summary of the 2021 TIF guidelines for TDT that focuses mainly on clinical practice issues and recommendations.
Correction: Endoscopistsʼ diagnostic accuracy in detecting upper gastrointestinal neoplasia in the framework of artificial intelligence studies
Authors: Leonardo Frazzoni, Giulio Antonelli, Julia Arribas, Diogo Libanio, Alanna Ebigbo, Fons van der Sommen, Albert Jeroen de Groof, Hiromu Fukuda, Masayasu Ohmori, Ryu Ishihara, Lianlian Wu, Honggang Yu, Yuichi Mori, Alessandro Repici, Jacques J. G. H. M. Bergman, Prateek Sharma, Helmut Messmann, Cesare Hassan, Lorenzo Fuccio, Mário Dinis-Ribeiro
Journal: Endoscopy (2022)

Correction to: Endoscopistsʼ diagnostic accuracy in detecting upper gastrointestinal neoplasia in the framework of artificial intelligence studiesEndoscopy 2022; 54(04): 403-411DOI: 10.1055/a-1500-3730
Highlights of This Issue
Journal: Clinical Cancer Research (2018)

Safety of Venetoclax Monotherapy in Relapsed/Refractory CLL Venetoclax, an oral BCL-2 inhibitor, is approved for treatment of patients with previously-treated chronic lymphocytic leukemia (CLL).With increased use of venetoclax in clinical practice, Davids and colleagues report on a comprehensive safety analysis of venetoclax monotherapy at the approved 400 mg daily dose in 350 patients enrolled in three phase-I or -II studies.The most common toxicities of venetoclax in relapsed/refractory CLL were mild gastrointestinal symptoms and transient, uncomplicated neutropenia.Tumor lysis syn-
David Oliver: Politicians’ abject failure to tackle the existential crisis in the NHS
Authors: David Oliver
Journal: BMJ (2022)

consultant in geriatrics and acute general medicine After the ousting of Boris Johnson as prime minister and the loss or replacement of many government ministers-including those at the Department of Health and Social Care-we're now faced with the ongoing instability of a Conservative Party leadership contest, the further ministerial churn that will follow, and a potential general election within 18 months or so.
The NADPH oxidase NOX4 regulates redox and metabolic homeostasis preventing HCC progression
Authors: Irene Peñuelas‐Haro, Rut Espinosa‐Sotelo, Eva Crosas‐Molist, Macarena Herranz‐Itúrbide, Daniel Caballero‐Díaz, Ania Alay, Xavier Solé, Emilio Ramos, Teresa Serrano, María L. Martínez‐Chantar, Ulla G. Knaus, José M. Cuezva, Antonio Zorzano, Esther Bertran, Isabel Fabregat
Journal: Hepatology (2022)

The NADPH oxidase NOX4 plays a tumor-suppressor function in HCC. Silencing NOX4 confers higher proliferative and migratory capacity to HCC cells and increases their in vivo tumorigenic potential in xenografts in mice. NOX4 gene deletions are frequent in HCC, correlating with higher tumor grade and worse recurrence-free and overall survival rates. However, despite the accumulating evidence of a protective regulatory role in HCC, the cellular processes governed by NOX4 are not yet understood. Accordingly, the aim of this work was to better understand the molecular mechanisms regulated by NOX4 in HCC in order to explain its tumor-suppressor action.Experimental models: cell-based loss or gain of NOX4 function experiments, in vivo hepatocarcinogenesis induced by diethylnitrosamine in Nox4 -deficient mice, and analyses in human HCC samples. Methods include cellular and molecular biology analyses, proteomics, transcriptomics, and metabolomics, as well as histological and immunohistochemical analyses in tissues. Results identified MYC as being negatively regulated by NOX4. MYC mediated mitochondrial dynamics and a transcriptional program leading to increased oxidative metabolism, enhanced use of both glucose and fatty acids, and an overall higher energetic capacity and ATP level. NOX4 deletion induced a redox imbalance that augmented nuclear factor erythroid 2-related factor 2 (Nrf2) activity and was responsible for MYC up-regulation.Loss of NOX4 in HCC tumor cells induces metabolic reprogramming in a Nrf2/MYC-dependent manner to promote HCC progression.